The present invention relates to a technique for treating a condition or disease in a human related to supranormal intracellular enzyme activity, and to a prodrug useful in such technique.
Ischemia, stroke, epilepsy, asthma and allergy are among the most frequently occurring disorders in humans.
Cerebrovascular disease, manifested e.g. as cerebral insufficiency, cerebral infarction, cerebral hemorrhage, or cerebral arteriovenous malformation, as well as stroke (ischemic lesions), constitutes the most common cause of neurological disability in developed countries.
Epilepsy affects about 2% of the population. No single drug controls all types of seizures, and different drugs or drug combinations are required for different patients.
Bronchial asthma is a reversible obstructive lung disorder. Asthma and allergies are very widespread diseases, especially in developed countries.
In spite of the obvious difference between the different diseases mentioned above, they are believed to be related to the phenomenon of cell hyperexcitation, in which cell membranes are broken down due to abnormal enzyme activity. Current pharmacological strategies are therefore aimed at inhibiting this degradative activity.
The cell damage occurring in ischemia may be secondary to the influx and/or intracellular release of Ca.sup.2+ ions (Siesjo and Smith, Arzneimittelforschung, 1991, 41(3A): 288-292). similarly, calcium influx appears to play an important role in the genesis of epileptic seizures, although a significant portion of intracellular calcium arrives from intracellular stores, and current research suggests that calcium entry blockers may have anticonvulsant activity (see e.g. Meyer, 1989, Brain Res. Rev. 14: 227-243).
Drugs which are currently or potentially useful for treatment of calcium associated disorders include (1) calcium channel blockers, (2) drugs affecting calcium economy by modification of calcium intracellular storage sites, and (3) intracellular calcium chelating agents. Calcium channel blockers used in clinical practice are represented by Verapamil, Nifedipine and Diltiazem. The major toxicities associated with the use of such compounds involve excessive vasodilation, negative inotropy, depression of the sinus nodal rate, and A-V nodal conductive disturbances. Drugs affecting calcium mobilization/sequestration, like calcium channel blockers, exhibit rather narrow specificity. There is no intracellular calcium chelating agent available for clinical requirements. Existing calcium chelators such as EGTA-AM, EDTA-AM, and BAPTA-AM are available as complex molecules, the hydrophobic part of which could be digested by cellular noninducible esterase, thus causing accumulation of chelator intracellular space, which is, however, random and uncontrolled, being unrelated to cell activity.
It would be useful to be able to selectively target diseased cells characterized by enzyme hyperactivity, so as to introduce a pharmacologically active molecule in the form of a prodrug into the cell, whereby such hyperactivity would act on the prodrug, so that the pharmacologically active molecule accumulates in the diseased cells rather than in the active cells. A non-limiting example of such pharmacologically active molecule is a calcium chelating agent, which would have many advantages over drugs presently used for the treatment of calcium associated disorders.
Intracellular calcium is an important determinant for cell death in organ hypothermic preservation for transplantation, and may also be relevant in organs protection (toxicology). Additionally, calcium precipitated cell disintegration accepted as a key event on lymphocyte and killer cell mediated damaging of the target cells. Lymphocyte-target interaction leads to sustained elevation of the intracellular calcium level and causes a cascade of destruction. Prevention of calcium entry improved the result of liver cold storage in UW solution (Rajab et al, Transplantation, 1991, 51(5): 965-7). Myocyte injury can be produced by sensitized cytotoxic T lymphocytes in vitro and is calcium dependent (Woodley et al, Circulation, 1991, 83(4): 1410-8). Studies illustrate reduced rejection rates in organ transplant patients treated with calcium channel blockers (Weir, Am J. Med., 1991, 90(5A): 32S-36S). Thus it will be apparent that the present invention has potential use (in the embodiment employing a calcium chelator) in relation to these circumstances.
It will also be self-evident that a similar concept can be applied to the treatment of conditions or diseases other than those related to the intramolecular level of Ca.sup.2+ ions. By way of example, if the active entity incorporated in the prodrug molecule is a protein kinase inhibitor, after administration of the prodrug the inhibitor would be accumulated in a cell exhibiting abnormal proliferation, thus providing potentially an important tool for use in antitumor therapy.